EP3287440A1 - Composé pyrrolidinoqie - Google Patents

Composé pyrrolidinoqie Download PDF

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Publication number
EP3287440A1
EP3287440A1 EP16783021.5A EP16783021A EP3287440A1 EP 3287440 A1 EP3287440 A1 EP 3287440A1 EP 16783021 A EP16783021 A EP 16783021A EP 3287440 A1 EP3287440 A1 EP 3287440A1
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group
compound
formula
compound represented
reaction
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EP3287440B1 (fr
EP3287440A4 (fr
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Tetsuya Ikemoto
Leopold Mpaka LUTETE
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms

Definitions

  • the present invention relates to a pyrrolidine compound, a method for producing the pyrrolidine compound, and use of the pyrrolidine compound as a catalyst.
  • 3-Formyl-2-hydroxypropanoic acid compounds are useful as an active ingredient for medicines, agrochemicals and the like or as an intermediate in the production of medicines, agrochemicals and the like.
  • an optically active form of the compound is useful as an intermediate in the production of vitamins including pantothenic acid.
  • the present invention provides: a novel catalyst; a method for producing the catalyst; and a method for producing a 3-formyl-2-hydroxypropanoic acid compound using the catalyst.
  • the present invention provides:
  • the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the C 1 -C 8 perfluoroalkyl group represented by Rf refers to a group in which all of hydrogen atoms in a C 1 -C 8 alkyl group are substituted by fluorine atoms, and specific examples thereof include a trifluoromethyl group, a pentafluoroethyl group and a nonafluorobutyl group.
  • Rf is preferably a C 1 -C 4 perfluoroalkyl group, more preferably a trifluoromethyl group.
  • the C 1 -C 12 alkyl group represented by R refers to a linear or branched alkyl group having 1 to 12 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, a 2,2-dimethylbutyl group, a heptyl group, an octyl group, a decyl group and a dodecyl group.
  • a C 1 -C 8 alkyl group is preferred, and a C 1 -C 4 alkyl group is particularly preferred.
  • the C 1 -C 12 alkoxy group represented by R refers to a linear or branched alkoxy group having 1 to 12 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, a neopentyloxy group, a hexyloxy group, an octyloxy group, a decyloxy group and a dodecyloxy group.
  • a C 1 -C 6 alkoxy group is preferred, and a C 1 -C 4 alkoxy group is particularly preferred.
  • a C 2 -C 7 alkoxycarbonyl group is preferred.
  • the C 1 -C 12 fluorinated alkyl group represented by R refers to a C 1 -C 12 alkyl group having a fluorine atom, and specific examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 3-fluoropropyl group, a 4-fluorobutyl group, an 8-fluorooctyl group and a 12-fluorododecyl group.
  • R is preferably a C 1 -C 12 alkyl group or a C 1 -C 12 fluorinated alkyl group, more preferably a C 1 -C 4 alkyl group or a C 1 -C 4 fluorinated alkyl group.
  • Particularly preferred specific examples of R include a methyl group, an ethyl group and a trifluoromethyl group.
  • m is preferably an integer of 0 to 2, more preferably 0.
  • Compound (1) has an asymmetric carbon atom, and therefore includes a compound represented by formula (1S) that is in an S steric configuration (hereinafter referred to as “compound (1S)”) and a compound represented by formula (1R) that is in an R steric configuration (hereinafter referred to as “compound (1R)").
  • Compound (1) can be used as a catalyst for the below-mentioned aldol reaction.
  • An optically active form of compound (1) can be used as an asymmetric catalyst.
  • compound (1) to be used in the asymmetric aldol reaction preferably has an enantiomeric excess of 90 ee% or more, more preferably 95 ee% or more.
  • Compound (1) can be synthesized by, for example, the following method. (wherein Rf, P G , R and m are as defined above.)
  • amino-group-protecting group examples include a C 1 -C 6 alkyl group (e.g., a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, a 2,2-dimethylbutyl group, a 2-ethylbutyl group), a C 2 -C 6 alkenyl group (e.g., an ethenyl group, a 1-propenyl group, a 2-propenyl group, a 2-methyl-1-propenyl group, a 1-butenyl group, a 3-methyl-2-butenyl group, a 2-pen
  • amino-group-protecting group examples include an acetyl group, a trifluoroacetyl group, a pivaloyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a benzhydryl group, a trityl group, a phthaloyl group, a p-toluenesulfonyl group and an o-nitrobenzenesulfonyl group.
  • the C 6 -C 10 aryl group refers to an aromatic monocyclic or polycyclic (condensed) hydrocarbon group having 6 to 10 carbon atoms, and specific examples thereof include a phenyl group, a 1-naphthyl group and a 2-naphthyl group.
  • the C 7 -C 14 aralkyl group refers to a group in which a C 6 -C 10 aryl group is bound to a C 1-4 alkyl group, and specific examples thereof include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a (naphthyl-1-yl)methyl group, a (naphthyl-2-yl)methyl group, a 1-(naphthyl-1-yl)ethyl group, a 1-(naphthyl-2-yl)ethyl group, a 2-(naphthyl-1-yl)ethyl group and a 2-(naphthyl-2-yl)ethyl group.
  • the tri-C 1 -C 6 alkylsilyl group refers to a silyl group having "three C 6 -C 6 alkyl groups", and specific examples thereof include a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group and a tert-butyldiethylsilyl group.
  • P G is preferably a C 7 -C 14 aralkyl group (preferably a benzyl group), a C 2 -C 7 alkoxycarbonyl group (preferably a tert-butoxycarbonyl group), a C 8 -C 15 aralkyloxycarbonyl group (preferably a benzyloxycarbonyl group) or a tri-C 1 -C 6 alkylsilyl group (preferably a trimethylsilyl group) in each of which a C 1 -C 6 alkyl group, a nitro group or a halogen atom may be bound on a benzene ring, and is particularly preferably a benzyl group.
  • Step 1 is a step of producing compound (3) from compound (2), and compound (3) can be produced by converting a hydroxyl group in compound (2) to a leaving group.
  • the leaving group include a halogen atom, a C 1 -C 6 alkanesulfonyloxy group (e.g., a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group), a C 1 -C 6 perfluoroalkanesulfonyloxy group (e.g., a trifluoromethanesulfonyloxy group, a pentafluoroethanesulfonyloxy group, a heptafluoropropanesulfonyloxy group), and a C 6 -C 10 arylsulfonyloxy group (e.g., a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group, an o-nitrobenzenesulfony
  • the leaving group is preferably a halogen atom, particularly preferably a chlorine atom.
  • the reaction for converting the hydroxyl group to the leaving group can be carried out by reacting a halogenating agent (e.g., thionyl chloride), a C 1 -C 6 alkanesulfonylating agent (e.g., methanesulfonyl chloride), a C 1 -C 6 perfluoroalkanesulfonylating agent (e.g., trifluoromethanesulfonyl chloride), a C 6 - 10 arylsulfonylating agent which may have a nitro group or the like (e.g., benzenesulfonyl chloride, p-toluenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride) or the like with compound (2).
  • the amount of the reagent to be used is preferably 1 to 10 moles, more preferably 1 to 3
  • the reaction may be carried out in the presence of a base.
  • a base include: an inorganic base, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; and an organic base, such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and imidazole.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBN 1,5-diazabicyclo[4.3.0]non-5-ene
  • the amount of the base to be used is preferably 10 moles or less, more preferably 1 to 5 moles, relative to 1 mole of compound (2), from the viewpoint of yield and economic performance.
  • the reaction is preferably carried out in a solvent.
  • the solvent include an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylene); a halogenated hydrocarbon solvent (e.g., chloroform, dichloromethane, carbon tetrachloride); an ether solvent (e.g., diethyl ether, tetrahydrofuran (THF), 1,4-dioxane); an aprotic polar solvent (e.g., dimethylformamide (DMF), dimethylacetamide) ; and a solvent mixture of two or more of the above-mentioned solvents.
  • aromatic hydrocarbon solvent e.g., toluene, benzene, xylene
  • a halogenated hydrocarbon solvent e.g., chloroform, dichloromethane, carbon tetrachloride
  • an ether solvent e.g., diethyl ether, tetrahydro
  • a halogenated hydrocarbon solvent is preferred, and chloroform is particularly preferred, from the viewpoint of achieving good reactivity and good yield.
  • the amount of the solvent to be used is preferably 2 to 50 mL, more preferably 3 to 10 mL, relative to 1 g of compound (2).
  • reaction is carried out by a method in which a reagent such as a halogenating agent and a sulfonylating agent is added to a mixture of compound (2), the base and the solvent and then the resultant solution is mixed.
  • a reagent such as a halogenating agent and a sulfonylating agent is added to a mixture of compound (2), the base and the solvent and then the resultant solution is mixed.
  • the reaction temperature may vary depending on the types of compound (2), the reagent, the base and the solvent, and is preferably within the range from -20 to 80°C, more preferably from -10 to 50°C.
  • the reaction time may vary depending on the types of compound (2), the reagent, the base and the solvent and the reaction temperature, and is preferably 0.5 to 24 hours, more preferably 1 to 6 hours.
  • the degree of progression of the reaction can be confirmed by an analysis means such as thin-layer chromatography, gas chromatography and high-performance liquid chromatography.
  • the isolation of compound (3) contained in a reaction mixture thus produced can be carried out by subjecting the reaction mixture to a work-up procedure (e.g., neutralization, extraction, washing with water, distillation, crystallization).
  • the purification of compound (3) can be carried out by subjecting compound (3) to an extraction purification treatment, a distillation treatment, an adsorption treatment with activated carbon, silica, alumina or the like, or a chromatography treatment by silica gel column chromatography or the like.
  • Compound (3) may be subjected to the subsequent step in the form of the reaction mixture. Particularly from the viewpoint of yield and economic performance, it is preferred to use the reaction mixture containing compound (3), which is produced in step 1, without any modification in the subsequent step.
  • Step 2 is a step for producing compound (4) by the reaction of compound (3) with ammonia, and compound (4) can be produced by converting the leaving group in compound (3) to an amino group with ammonia.
  • Ammonia is generally used in the form of an aqueous solution or a solution in an alcohol (e.g., methanol, ethanol, isopropyl alcohol). Water or the alcohol may double as a solvent.
  • the amount of ammonia to be used is preferably 2 to 200 moles, more preferably 5 to 100 moles, relative to 1 mole of compound (3), from the viewpoint of yield and economic performance.
  • reaction is carried out by a method in which ammonia is added to the reaction mixture containing compound (3) and then the resultant solution is mixed.
  • the reaction temperature may vary depending on the types of compound (3) and the solvent, and is preferably within the range from 0 to 80°C, more preferably from 10 to 50°C.
  • the reaction time may vary depending on the types of compound (3) and the solvent and the reaction temperature, and is preferably 0.5 to 24 hours, more preferably 1 to 8 hours.
  • the degree of progression of the reaction can be confirmed by an analysis means such as thin-layer chromatography, gas chromatography and high-performance liquid chromatography.
  • the isolation of compound (4) contained in a reaction mixture thus produced can be carried out by subjecting the reaction mixture to a work-up procedure (e.g., neutralization, extraction, washing with water, distillation, crystallization).
  • the purification of compound (4) can be carried out by subjecting compound (4) to an extraction purification treatment, a distillation treatment, an adsorption treatment with activated carbon, silica, alumina or the like, or a chromatography treatment by silica gel column chromatography or the like.
  • Compound (4) may be subjected to the subsequent step in the form of the reaction mixture.
  • Step 3 is a step for producing compound (5) from compound (4), and compound (5) can be produced by reacting compound (4) with a C 1 -C 8 perfluoroalkanesulfonylating agent (e.g., a trifluoromethanesulfonylating agent).
  • a C 1 -C 8 perfluoroalkanesulfonylating agent e.g., a trifluoromethanesulfonylating agent.
  • C 1 -C 8 perfluoroalkanesulfonylating agent examples include trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, pentafluoroethanesulfonyl chloride and nonafluorobutanesulfonyl chloride.
  • the amount of the C 1 -C 8 perfluoroalkanesulfonylating agent to be used is preferably 1 to 2 moles, more preferably 1.05 to 1.4 moles, relative to 1 mole of compound (4), from the viewpoint of yield and economic performance.
  • the reaction is generally carried out in the presence of a base.
  • a base include: an inorganic base, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; and an organic base, such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN and imidazole, preferably triethylamine.
  • the amount of the base to be used is preferably 1 to 3 moles, more preferably 1.2 to 2 moles, relative to 1 mole of compound (4), from the viewpoint of yield and economic performance.
  • the reaction is generally carried out in a solvent.
  • the solvent include an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylene); a halogenated hydrocarbon solvent (e.g., chloroform, dichloromethane, carbon tetrachloride) ; an ether solvent (e.g., diethyl ether, THF); an aprotic polar solvent (e.g., DMF, dimethylacetamide) ; and a solvent mixture of two or more of the above-mentioned solvents.
  • a halogenated hydrocarbon solvent is preferred, and chloroform is particularly preferred, from the viewpoint of achieving good reactivity and good yield.
  • the amount of the solvent to be used is preferably 3 to 50 mL, more preferably 5 to 25 mL, relative to 1 g of compound (4).
  • reaction is carried out by a method in which a trifluoromethanesulfonylating agent is added to a mixture of compound (4), the base and the solvent and then the resultant solution is mixed.
  • the reaction temperature may vary depending on the types of compound (4), the trifluoromethanesulfonylating agent, the base and the solvent, and is preferably within the range from -20 to 80°C, more preferably from -10 to 50°C.
  • the reaction time may vary depending on the types of compound (4), the trifluoromethanesulfonylating agent, the base and the solvent and the reaction temperature, and is preferably 1 to 24 hours, more preferably 3 to 12 hours.
  • the degree of progression of the reaction can be confirmed by an analysis means such as thin-layer chromatography, gas chromatography and high-performance liquid chromatography.
  • the isolation of compound (5) contained in a reaction mixture thus produced can be carried out by subjecting the reaction mixture to a work-up procedure (e.g., neutralization, extraction, washing with water, distillation, crystallization).
  • the purification of compound (5) can be carried out by subjecting compound (5) to an extraction-purification procedure, a distillation procedure, an adsorption procedure with activated carbon, silica, alumina or the like, or a chromatography procedure by silica gel column chromatography or the like.
  • Compound (5) may be subjected to the subsequent step in the form of the reaction mixture.
  • Step 4 is a step for producing compound (5) by the reaction of compound (3) with trifluoromethanesulfonamide or a salt thereof.
  • An example of the salt of trifluoromethanesulfonamide is a lithium salt.
  • Compound (3) may be used in the form of the reaction mixture produced in step 1. In this case, it is desirable to remove the remaining halogenating agent.
  • the amount of the trifluoromethanesulfonamide or a salt thereof to be used is preferably 0.8 to 3 moles, more preferably 1.1 to 2 moles, relative to 1 mole of compound (3), from the viewpoint of yield and economic performance.
  • the reaction is generally carried out in the presence of a base.
  • a base include: an inorganic base, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; and an organic base, such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN and imidazole.
  • the amount of the base to be used is preferably 1 to 10 moles, more preferably 1.2 to 5 moles, relative to 1 mole of compound (3), from the viewpoint of yield and economic performance.
  • the reaction is preferably carried out in a solvent.
  • the solvent include an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylene); a halogenated hydrocarbon solvent (e.g., chloroform, dichloromethane, carbon tetrachloride); an ether solvent (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane); an aprotic polar solvent (e.g., DMF, dimethylacetamide); and a solvent mixture of two or more of the above-mentioned solvents.
  • aromatic hydrocarbon solvent e.g., toluene, benzene, xylene
  • a halogenated hydrocarbon solvent e.g., chloroform, dichloromethane, carbon tetrachloride
  • an ether solvent e.g., diethyl ether, tetrahydrofuran, 1,4-diox
  • a halogenated hydrocarbon solvent is preferred, and chloroform is particularly preferred, from the viewpoint of achieving good reactivity and good yield.
  • the amount of the solvent to be used is preferably 2 to 100 mL, more preferably 2.5 to 10 mL, relative to 1 g of compound (3).
  • reaction is carried out by a method in which trifluoromethanesulfonamide or a salt thereof and the base are added to a mixture of compound (3) and the solvent and then the resultant solution is mixed.
  • the reaction temperature may vary depending on the types of compound (3), the base and the solvent, and is preferably within the range from 0 to 120°C, more preferably from 20 to 80°C.
  • the reaction time may vary depending on the types of compound (3), the base and the solvent and the reaction temperature, and is preferably 0.5 to 24 hours, more preferably 1 to 8 hours.
  • the degree of progression of the reaction can be confirmed by an analysis means such as thin-layer chromatography, gas chromatography and high-performance liquid chromatography.
  • the isolation of compound (5) contained in a reaction mixture thus produced can be carried out by subjecting the reaction mixture to a work-up procedure (e.g., neutralization, extraction, washing with water, distillation, crystallization).
  • the purification of compound (5) can be carried out by subjecting compound (5) to an extraction-purification procedure, a distillation procedure, an adsorption procedure with activated carbon, silica, alumina or the like, or a chromatography procedure by silica gel column chromatography or the like.
  • Compound (5) may be subjected to the subsequent step in the form of the reaction mixture.
  • Step 5 is a step for producing compound (1) by deprotecting compound (5).
  • the deprotection can be carried out by, for example, a known method disclosed in " Protective Groups in Organic Synthesis", attributed to T. W. Greene and P. G. M. Wuts (published by Wiley-Interscience, fourth edition, 2006 ).
  • the deprotection can be carried out by reacting compound (5) in the presence of a catalyst and a hydrogen source.
  • the catalyst include palladium-carbon, palladium black, palladium chloride, palladium hydroxide, rhodium-carbon, platinum oxide, platinum black, platinum-palladium, raney nickel and raney cobalt.
  • the amount of the catalyst to be used is preferably 0.001 to 0.5 g, more preferably 0.05 to 0.15 g, relative to 1 g of compound (5), from the viewpoint of yield and economic performance.
  • the hydrogen source include a hydrogen gas, ammonium formate and cyclohexadiene.
  • the amount of the hydrogen source to be used is preferably 1 to 5 moles, more preferably 1 to 3 moles, relative to 1 mole of compound (5).
  • the hydrogen gas is generally used under a pressure of 0.1 to 1.0 Mpa, due to the limitation with respect to experimental facilities.
  • the reaction is carried out in a solvent.
  • the solvent include an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylene); an aliphatic hydrocarbon solvent (e.g., hexane, heptane, cyclohexane); an alcohol solvent (e.g., methanol, ethanol); an ether solvent (e.g., diethyl ether, THF); an ester solvent (e.g., ethyl acetate, isopropyl acetate) ; water; or a mixture of two or more of these solvents.
  • an alcohol solvent is preferred, and methanol is particularly preferred, from the viewpoint of achieving good reactivity and good yield.
  • the reaction is carried out by a method in which the compound (5), the catalyst and the solvent are mixed together, then the hydrogen source is added to the resultant mixture and then the resultant solution is mixed, or the like.
  • the reaction temperature may vary depending on the types of compound (5), the catalyst, the hydrogen source and the solvent, and is preferably within the range from 0 to 60°C, more preferably from 10 to 50°C.
  • the reaction time may vary depending on the types of compound (5), the catalyst, the hydrogen source and the solvent and the reaction temperature, and is preferably 1 to 20 hours, more preferably 1 to 10 hours.
  • the degree of progression of the reaction can be confirmed by an analysis means such as thin-layer chromatography, gas chromatography and high-performance liquid chromatography.
  • the isolation of compound (1) contained in a reaction mixture thus produced can be carried out by subjecting the reaction mixture to a work-up procedure (e.g., neutralization, extraction, washing with water, distillation, crystallization).
  • the purification of compound (1) can be carried out by subjecting compound (1) to an extraction-purification procedure, a distillation procedure, an adsorption procedure with activated carbon, silica, alumina or the like, or a chromatography procedure by silica gel column chromatography or the like.
  • Compound (2) to be used in the production of compound (1) can be produced through, for example, the following route.
  • an optically active form of compound (2) can be produced.
  • Compound (1) can be used in an aldol reaction as shown below. Particularly, an optically active form of compound (1) can be used in an asymmetric aldol reaction to produce an optically active form of compound (III).
  • Examples of the protecting group for a carboxyl group (hereinafter referred to as "carboxyl-group-protecting group”) represented by R 1 include a C 1 -C 6 alkyl group, a C 7 -C 14 aralkyl group, a phenyl group, a trityl group and a tri-C 1 -C 6 alkylsilyl group, and specific example thereof include a methyl group, an ethyl group, a tert-butyl group, a benzyl group, a trityl group, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group and a tert-butyldiethylsilyl group.
  • R 1 is preferably a C 1 -C 6 alkyl group, more preferably a C 1 -C 4 alkyl group, particularly preferably an ethyl group.
  • hydroxyl-group-protecting group represented by R 2
  • R 2 Specific examples of the protecting group for a hydroxyl group (hereinafter referred to as "hydroxyl-group-protecting group") represented by R 2 include a C 1 -C 6 alkyl group, a phenyl group, a trityl group, a C 7 -C 14 aralkyl group, a formyl group, a C 2 -C 7 alkylcarbonyl group, a benzoyl group, a C 8 -C 15 aralkylcarbonyl group, a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, a tri-C 1 -C 6 alkylsilyl group, a succinimidoxycarbonyl group, a C 7 -C 11 arylcarbonyl group, a C 7 -C 11 aryloxycarbonyl group and a C 8 -C 15 aralkyloxycarbonyl group.
  • hydroxyl-group-protecting group examples include a benzyl group, an acetyl group, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiethylsilyl group, a succinimidoxycarbonyl group, a phenoxycarbonyl group and a benzyloxycarbonyl group.
  • R 2 is preferably a C 7 -C 14 aralkyl group, particularly preferably a benzyl group.
  • the above-mentioned aldol reaction is a reaction in which compound (I), which is a glyoxylic acid derivative, or a polymer thereof with compound (II) in the presence of compound (1) to produce compound (III).
  • the polymer of compound (I) is a compound represented by formula (I-1): (wherein n1 represents an integer of 2 or more; and R 1 is as defined above) or a cyclic polymer compound, and a typical example of the cyclic polymer compound is a trimer represented by the following formula: (wherein R 1 is as defined above).
  • Compound (I) is commercially available, and a commercially available product can be used without any modification.
  • Each of compound (I) and a polymer thereof is also commercially available in the form of a solution (e.g., a solution in toluene (also referred to as a "toluene solution”, hereinafter)), and the commercially available toluene solution can be used without any modification.
  • a solution in toluene also referred to as a "toluene solution”, hereinafter
  • the aldol reaction is preferably carried out in a solvent.
  • the solvent include: an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylene); an aliphatic hydrocarbon solvent (e.g., hexane, heptane, cyclohexane); an alcohol solvent (e.g., methanol, ethanol, 2-propanol, 2-methyl-2-propanol); a halogenated hydrocarbon solvent (e.g., chloroform, dichloromethane, carbon tetrachloride, 1-chlorobutane); an ether solvent (e.g., diethyl ether, THF, 2-methyltetrahydrofuran, 1,2-dimethoxyethane (ethylene glycol dimethyl ether (EGDE)), methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, dibutyl ether, cyclopen
  • an aromatic hydrocarbon solvent an alcohol solvent; a halogenated hydrocarbon solvent; an ether solvent; a nitrile solvent; water; a solvent mixture of the aforementioned solvents, and the like are preferred.
  • At least one solvent selected from the group consisting of NMP, DMI, DMF, acetonitrile, THF, EGDE, toluene, chloroform, methanol and water it is more preferred to use a mixture of two solvents selected from the aforementioned solvents, and it is particularly preferred to use a solvent mixture of water and NMP or water and DMI.
  • the amount of compound (I) to be used is preferably 0.5 to 10 moles, more preferably 0.8 to 2 moles, relative to 1 mole of compound (II), from the viewpoint of economic performance.
  • the aldol reaction can be carried out by: a method in which compound (II), compound (1) and the solvent are added to a polymer of compound (I) and the resultant solution is mixed; a method in which a polymer of compound (I), compound (1) and the solvent are mixed together, then compound (II) is added to the solution, and the resultant solution is mixed; a method in which compound (II), compound (1) and the solvent are mixed together, then a polymer of compound (I) is added to the solution, and the resultant solution is mixed; and the like.
  • the aldol reaction by: a method in which compound (II), compound (1) and the solvent are mixed together, then a polymer of compound (I) is added to the solution and then the resultant solution was mixed; or a method in which a polymer of compound (I), compound (1) and the solvent are mixed together, then the compound (II) is added to the solution and then the resultant solution is mixed.
  • the amount of compound (1) to be used is preferably 0.1 to 30 mol%, more preferably 0.5 to 15 mol%, relative to the amount of compound (II), from the viewpoint of yield and economic performance.
  • the reaction temperature may vary depending on the types of compound (II), and is preferably within the range from -20 to 100°C, more preferably from -10 to 40°C.
  • the reaction time may vary depending on the types of compound (II) and the reaction temperature, and is preferably 1 to 100 hours, more preferably 3 to 50 hours.
  • the degree of progression of the reaction can be confirmed by an analysis means such as thin-layer chromatography, gas chromatography and high-performance liquid chromatography.
  • the isolation of compound (III) contained in a reaction mixture thus produced can be carried out by subjecting the reaction mixture to a work-up procedure (e.g., neutralization, extraction, washing with water, distillation, crystallization).
  • the purification of compound (III) can be carried out by subjecting compound (III) to an extraction-purification procedure, a distillation procedure, an adsorption procedure with activated carbon, silica, alumina or the like, or a chromatography procedure by silica gel column chromatography or the like.
  • an optically active form of compound (1) in which m is 0 or an optically active form of compound (1) in which R is a methyl group, an ethyl group or a trifluoromethyl group depending on the types of compound (II), and it is particularly preferred to use an optically active form of compound (1) in which m is 0.
  • an optically active form of the anti-form compound (III), i.e., a compound represented by formula (IIIR) (hereinafter referred to as “compound (IIIR) ”) or a compound represented by formula (IIIS) (hereinafter referred to as “compound (IIIS)”): can be produced preferentially.
  • Compound (IIIR) is produced preferentially in the case where an S-form of compound (1) is used as a catalyst
  • compound (IIIS) is produced preferentially in the case where an R-form of compound (1) is used as a catalyst, wherein the diastereomer ratio (i.e., a syn/anti ratio) can become 50/50 or more. It becomes possible to achieve such selectivity that the diastereomer ratio (syn/anti ratio) is 20/80 or more, more preferably 10/90 or more.
  • the enantiomeric excess can become 50 ee% or more. It becomes possible to achieve such selectivity that the enantiomeric excess is 80 ee% or more, more preferably 90 ee% or more.
  • an optically active form of compound (III) to an optically active form of a corresponding acetal compound, i.e., a compound represented by formula (IV): (wherein R 1 and R 2 are as defined above; and R 3 represents a C 1 -C 12 alkyl group, a C 2 -C 12 alkenyl group, a C 2 -C 12 alkynyl group or a C 7 -C 14 aralkyl group) (hereinafter referred to as "compound (IV)").
  • R 3 is preferably a C 1 -C 12 alkyl group, more preferably a C 1 -C 8 alkyl group, still more preferably a C 1 -C 4 alkyl group, still more preferably a C 1 -C 3 alkyl group, particularly preferably a methyl group.
  • An optically active form of compound (IV) can be produced by reacting a reaction mixture (which contains an optically active form of compound (III) and is obtained after the completion of the asymmetric aldol reaction) or an optically active form of compound (III) (which is isolated but is not purified yet) with an alcohol compound represented by the following formula: R 3 OH (wherein R 3 is as defined above) or an orthoformate compound represented by the following formula: HC(OR 3 ) 3 (wherein R 3 is as defined above) in the presence of an acid catalyst.
  • the amount of the alcohol compound to be used is preferably 2 to 200 moles, more preferably 10 to 100 moles, relative to 1 mole of the optically active form of compound (III), from the viewpoint of yield and economic performance.
  • the alcohol compound is generally used as a reaction solvent.
  • the acid catalyst examples include pyridinium p-toluenesulfonate, and p-toluenesulfonic acid or a monohydrate thereof. From the viewpoint of reaction selectivity, pyridinium p-toluenesulfonate is preferred.
  • the amount of the acid catalyst to be used is preferably 0.01 to 1 moles, more preferably 0.01 to 0.1 moles, relative to 1 mole of the optically active form of compound (III), from the viewpoint of reactivity and economic performance.
  • the reaction can be carried out by: a method in which an alcohol compound and an acid catalyst are added to an optically active form of compound (III), which is isolated but is not purified yet, and then the resultant solution is mixed; a method in which an acid catalyst is added to an optically active form of compound (III), which is isolated but is not purified yet, then an alcohol compound is added to the solution, and the resultant solution is mixed; or the like. From the viewpoint of simplifying the operations, it is preferred to carry out the reaction by a method in which an alcohol compound and an acid catalyst are added to an optically active form of compound (III), which is isolated but is not purified yet, and then the resultant solution is mixed.
  • the reaction temperature may vary depending on the types of the alcohol compound and the acid catalyst, and is preferably within the range from 0 to 100°C, more preferably from 20 to 80°C, particularly preferably from 40 to 60°C.
  • the reaction time may vary depending on the types of the alcohol compound and the acid catalyst and the reaction temperature, and is preferably 10 minutes to 50 hours, more preferably 30 minutes to 20 hours, particularly preferably 1 to 10 hours.
  • the degree of progression of the reaction can be confirmed by an analysis means such as thin-layer chromatography, gas chromatography and high-performance liquid chromatography.
  • the amount of the orthoformate compound to be used is preferably 1 to 50 moles, more preferably 3 to 30 moles, relative to 1 mole of the optically active form of compound (III), from the viewpoint of yield and economic performance.
  • the acid catalyst examples include p-toluenesulfonic acid or a monohydrate thereof and pyridinium p-toluenesulfonate. From the viewpoint of yield and economic performance, p-toluenesulfonic acid or a monohydrate thereof is preferred.
  • the amount of the acid catalyst to be used is preferably 0.01 to 1 mole, more preferably 0.01 to 0.2 mole, relative to 1 mole of the optically active form of compound (III), from the viewpoint of the reaction rate.
  • the reaction can be carried out by: a method in which an orthoformate compound and an acid catalyst are added to a reaction mixture containing an optically active form of compound (III), which is obtained after the completion of the asymmetric aldol reaction, and then the resultant solution is mixed; a method in which an acid catalyst is added to a reaction mixture containing an optically active form of compound (III), which is obtained after the completion of the aldol reaction, then an orthoformate compound is added to the solution, and the resultant solution is mixed; or the like.
  • the reaction temperature may vary depending on the types of the orthoformate compound and the acid catalyst, and is preferably within the range from 0 to 100°C, more preferably from 10 to 40°C, particularly preferably from 20 to 30°C.
  • the reaction time may vary depending on the types of the orthoformate compound and the acid catalyst and the reaction temperature, and is preferably 10 minutes to 50 hours, more preferably 30 minutes to 20 hours, particularly preferably 1 to 10 hours.
  • the degree of progression of the reaction can be confirmed by an analysis means such as thin-layer chromatography, gas chromatography and high-performance liquid chromatography.
  • the isolation of the optically active form of compound (IV), which is contained in a mixture produced by the reaction with the alcohol compound or the orthoformate compound, can be carried out by subjecting the reaction mixture to a work-up procedure (e.g., neutralization, extraction, washing with water, distillation, crystallization).
  • the purification of the optically active form of compound (IV) can be carried out by subjecting the optically active form of compound (IV) to a recrystallization procedure, an extraction-purification procedure, a distillation procedure, an adsorption procedure with activated carbon, silica, alumina or the like, or a chromatography procedure by silica gel column chromatography or the like.
  • the optically active form of compound (IV) thus produced is measured with respect to the diastereomer ratio (syn/anti ratio) and enantiomeric excess thereof.
  • the measured diastereomer ratio (syn/anti ratio) and enantiomeric excess correspond to those of the optically active form of the compound (III) .
  • Ethyl glyoxylate was used in the form of a 50.8% toluene solution of a polymer purchased from JIAXING JLIGHT. All of liquid aldehydes and solvents other than ethyl glyoxylate were distilled before use.
  • FT-IR spectra were measured with JASCO FT/IR-410 spectrometer.
  • HPLC analysis was carried out using CHIRALCEL OB-H (0.46 cm ⁇ 25 cm), CHIRALPAK IA (0.46 cm ⁇ 25 cm) and CHIRALPAK IB (0.46 cm ⁇ 25 cm) while monitoring the UV detection with HITACHI Elite LaChrom Series HPLC.
  • the diastereomer ratio was measured by HPLC using reverse-phase column column pack C 18 MGIII (150 ⁇ 4.6 mm, 5 ⁇ m) under the following conditions.
  • the enantiomeric excess was measured by HPLC with arranging reverse-phase column CHIRALPAK AS-RH (4.6 mm ⁇ 150 mm, 5 ⁇ m) and L-column ODS (4.6 mm ⁇ 15 mm, 5 ⁇ m) tandemly under the following conditions.
  • a compound II (1258.7 mg, a 70% toluene solution, 5.0 mmol) was added to a mixture of a solution of a polymer of compound (I) (1225.1 mg, a 50.8% toluene solution, 6.0 mmol), a catalyst a (78.5 mg, 0.15 mmol), water (270 ⁇ L) and a solvent shown in Table 2 (1.3 mL).
  • the resultant mixture was stirred at room temperature (25-35°C). After 20 hours, trimethyl orthoformate (10.6 g, 100 mmol) and p-toluenesulfonic acid monohydrate (47.6 mg, 0.25 mmol) were added sequentially to the mixture, and the resultant mixture was stirred at room temperature for 3 hours.
  • each of the yields of Examples 4-1 and 4-4 was a yield of the isolated compound IV, and the yield of each of other Examples was determined by adding biphenyl (154.2 mg, 1.0 mmol) as an internal reference to the reaction mixture and was measured by HPLC. The diastereomer ratio and the enantiomeric excess were determined in the same manner as in Example 2.
  • p-Fluorophenyl magnesium bromide 140 ml, 140 mmol was added dropwise to a solution of N-benzylproline methyl ester (11 g, 50 mmol) in THF (150 ml), which was cooled to 0°C, and the resultant mixture was refluxed for three hours after the completion of the dropwise addition.
  • the mixture was cooled to room temperature, then an aqueous ammonium chloride solution (75 ml) was added to the mixture, and then 1 N hydrochloric acid (75 ml) was further added to the mixture.
  • the pH value of the mixture was adjusted to about 7.5 with a 2 N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate (3 ⁇ 150 mL). An organic layer was washed with brine (2 ⁇ 150 mL), the washed solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A slurry prepared by adding ethyl acetate (10 mL) and heptane (200 mL) to the residue was refluxed for 1 hour.
  • the resultant solution was air-cooled to produce a solid material, and the solid material was filtrated, was then washed with ethyl acetate/heptane (1/20, 150 mL) and then dried to produce a desired material as a yellow solid material (14.5 g, 75%).
  • the present invention provides compound (1) which can be used as a catalyst.
  • compound (1) which can be used as a catalyst.
  • an aldol reaction is carried out in the presence of compound (1), a 3-formyl-2-hydroxypropanoic acid compound can be produced.
  • an optically active form of compound (1) is used, an optically active form of a 3-formyl-2-hydroxypropanoic acid compound can be produced with good selectivity.

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